Prostate cancer is one of the most common malignancies of males in western countries, accounting for 36 percent of all male cancers and 13 percent of male cancer-related deaths. In spite of the magnitude of the problem which this malignancy presents, an understanding of the molecular mechanisms underlying susceptibility remains elusive. Complex segregation analyses suggest the existence of dominant high-penetrant susceptibility alleles, which may account for up to 10 percent of all prostate cancer. During this past grant period, the applicant has performed a genome-wide scan on 163 kindreds with three or more affected men with prostate cancer, as well as analyzed several chromosomal regions reported by others to demonstrate linkage. By the end of the current grant period, they will have completed the genome-wide scan of their families. Although linkage analysis of hereditary prostate cancer (HPC) is complicated by a number of barriers, including potentially extensive genetic heterogeneity, high phenocopy rates, and lack of fully informative pedigrees, a number of research groups (including the Mayo Clinic) have implicated four loci (three on chromosome 1 and one on the X chromosome) as harboring HPC genes. Additionally, the P.I. has demonstrated linkage to an unreported region on chromosome 20, at 20q13. In spite of the progress made, these five loci still account for less than half of the HPC cases. With the completion of the genome-wide scan, as well as the completion of similar analyses from other groups, it is likely that other chromosomal regions will be identified. It is noticed that none of the putative susceptibility genes from these regions have been identified. Thus, the P.I. proposed the following specific aims: 1) Complete the statistical analysis of the genome-wide scan and identify additional regions of linkage for more detailed analyses; 2) Define the narrowest genetic and physical interval for those regions demonstrating the strongest evidence of linkage in the Mayo families; 3) Identify candidate genes that map to these region(s), especially to chromosome 20ql3; and 4) Analyze and characterize genes from the regions of interest for their involvement in hereditary prostate cancer. The potential impact of the discoveries of cancer susceptibility genes on cancer prevention and early detection, leading to increased likelihood of cure is great. In the case of prostate cancer, it is clear that early, localized disease is highly curable.